Cellular manganese content is developmentally regulated in human dopaminergic neurons

Kevin K. Kumar, Edward W. Lowe, Asad A. Aboud, M. Diana Neely, Rey Redha, Joshua A. Bauer, Mihir Odak, C. David Weaver, Jens Meiler, Michael Aschner, Aaron B. Bowman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington's disease. Handling of other essential metals (e.g. iron and zinc) occurs via complex intracellular signaling networks that link metal detection and transport systems. However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content in a mouse striatal neuron cell line. Following stringent validation assays and chemical informatics, we obtained a chemical 'toolbox' of 41 small molecules with diverse structure-activity relationships that can alter intracellular Mn levels under biologically relevant Mn exposures. We utilized this toolbox to test for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules. This work demonstrates cell-level regulation of Mn content across neuronal differentiation.

Original languageEnglish (US)
Article number6801
JournalScientific Reports
Volume4
DOIs
StatePublished - Oct 28 2014

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Dopaminergic Neurons
Manganese
Metals
Corpus Striatum
Informatics
Huntington Disease
Environmental Exposure
Parkinsonian Disorders
Structure-Activity Relationship
Basal Ganglia
Neurodegenerative Diseases
Zinc
Homeostasis
Iron

ASJC Scopus subject areas

  • General

Cite this

Kumar, K. K., Lowe, E. W., Aboud, A. A., Neely, M. D., Redha, R., Bauer, J. A., ... Bowman, A. B. (2014). Cellular manganese content is developmentally regulated in human dopaminergic neurons. Scientific Reports, 4, [6801]. https://doi.org/10.1038/srep06801

Cellular manganese content is developmentally regulated in human dopaminergic neurons. / Kumar, Kevin K.; Lowe, Edward W.; Aboud, Asad A.; Neely, M. Diana; Redha, Rey; Bauer, Joshua A.; Odak, Mihir; Weaver, C. David; Meiler, Jens; Aschner, Michael; Bowman, Aaron B.

In: Scientific Reports, Vol. 4, 6801, 28.10.2014.

Research output: Contribution to journalArticle

Kumar, KK, Lowe, EW, Aboud, AA, Neely, MD, Redha, R, Bauer, JA, Odak, M, Weaver, CD, Meiler, J, Aschner, M & Bowman, AB 2014, 'Cellular manganese content is developmentally regulated in human dopaminergic neurons', Scientific Reports, vol. 4, 6801. https://doi.org/10.1038/srep06801
Kumar, Kevin K. ; Lowe, Edward W. ; Aboud, Asad A. ; Neely, M. Diana ; Redha, Rey ; Bauer, Joshua A. ; Odak, Mihir ; Weaver, C. David ; Meiler, Jens ; Aschner, Michael ; Bowman, Aaron B. / Cellular manganese content is developmentally regulated in human dopaminergic neurons. In: Scientific Reports. 2014 ; Vol. 4.
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